MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis.
Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Defects include a change either in the intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade. The cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP. The above-mentioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP-bound state to the GTP-bound state. This signal is an absolute prerequisite for proliferation in most cell types. Defects in this signaling system, especially in the deactivation of the Ras-GTP complex, are common in cancers, and lead to the signaling cascade below Ras being chronically activated. Activated Ras leads in turn to the activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEK1 and MEK2) which then activates MAP kinase, ERK (ERK1 and ERK2). Activation of MAP kinase by mitogens appears to be essential for proliferation; constitutive activation of this kinase is sufficient to induce cellular transformation. Blockade of downstream Ras signaling, for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants. Although Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism. Once activated, Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, S218 and S222 in the case of MEK-1, which are the prerequisite for activation of MEK as a kinase. MEK in turn phosphorylates MAP kinase on both a tyrosine, y185, and a threonine residue, T183, separated by a single amino acid. This double phosphorylation activates MAP kinase at least 100-fold. Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase. In fact, no substrate for MEK other than the MAP kinase, ERK, has been demonstrated to date and MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of MEK are suggestive that it may have enough difference in its mechanism of action to other protein kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP binding site, may be found.
The invention features compounds of formulae (II) below, such as formula(I): 
In formulae (I) and (II), W is OR1, NR2OR1, NRARB, NR2NRARB, or NR2(CH2)2-4 NRARB. R1 is H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, phenyl, (phenyl)C1-4 alkyl, (phenyl)C3-4 alkenyl, (phenyl)C3-4 alkynyl, (C3-8 cycloalkyl)C1-4 alkyl, (C3-8 cycloalkyl)C3-4 alkenyl, (C3-8 cycloalkyl)C3-4 alkynyl, C3-8 heterocyclic radical, (C3-8 heterocyclic radical)C1-4 alkyl, (C3-8 heterocyclic radical)C3-4 alkenyl, (C3-8 heterocyclic radical)C3-4 alkynyl, or (CH2)2-4NRARB. R2 is H, phenyl, C1-4 alkyl, C3-4 alkenyl C3-8 alkynyl, C3-8 cycloalkyl, or (C3-8 cycloalkyl)C1-4 alkyl. RA is H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, phenyl, (C3-8 cycloalkyl)C1-4 alkyl, (C3-8 cycloalkyl)C3-4 alkenyl, (C3-8 cycloalkyl)C3-4 alkynyl, C3-8 heterocyclic radical, (C3-8 heterocyclic radical)C1-4 alkyl, (aminosulfonyl)phenyl, [(aminosulfonyl)phenyl]C1-4 alkyl, (aminosulfonyl)C1-6 alkyl, (aminosulfonyl)C3-6 cycloalkyl, or [(aminosulfonyl)C3-6 cycloalkyl]C1-4 alkyl. RB is H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, or C6-8 aryl. R3 is halo, NO2, SO2NRI(CH2)2-4NRERF, SO2NRI RK or (CO)T. T is C1-8 alkyl, C3-8 cycloalkyl, (NRERF)C1-4 alkyl, ORF, NRI(CH2)2-4NRERF, or NRERF. R4 is H or F; R5 is H, methyl, halo, or NO2; and R6 is H, methyl, halo, or NO2. In formula (II), Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. Each of R7 and R8 is independently selected from H, halo, C1-4 alkyl, SO2NRJ (CH2)2-4NRGRH, (CO)(CH2)2-4NRGRH, (CO)NRJ(CH2)2-4NRGRH, (CO)O(CH2)2-4NRGRH, SO2NRGRH, and (CO)NRGRH. However, where Ar is a pyridyl, each of R7 and R8 is H. Each of RC, RD, RE, RF, RG, and RH is independently selected from H, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, C3-6 cycloalkyl, and phenyl. Each of NRCRD, NRERF, and NRGRH can also be independently morpholinyl, piperazinyl, pyrrolidinyl, or piperadinyl. Each of RI and RJ is independently H. methyl, or ethyl. RK is C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, C3-6 cycloalkyl, or phenyl. X is O, S, or NH. Finally, each hydrocarbon radical or heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkenyl, C1-4 alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO2, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 3 substituents independently selected from halo, C1-2 alkyl, hydroxyl, amino, and NO2. In addition to the above compounds, the invention also provides a pharmaceutically acceptable salt or C1-7 ester thereof.
The invention also relates to a pharmaceutical composition including (a) a diarylamine (e.g., of formula I) and (b) a pharmaceutically acceptable carrier.
The invention further relates to a method for treating proliferative diseases, such as cancer, restenosis, psoriasis, autoimmune disease, and atherosclerosis. Other aspects of the invention include methods for treating MEK-related cancer, tumors of the breast, lung, colorectal, pancreas, prostate, brain, kidney, or ovary, and other solid or hematopoietic cancers. Further aspects of the invention include methods for treating or reducing the symptoms of xenograft (organ, cell(s), limb, skin, or bone marrow transplant) rejection, osteoarthritis, rheumatoid arthritis, cystic fibrosis, hepatomegaly, cardiomegaly, complications of diabetes (including diabetic nephropathy and diabetic retinopathy), stroke, heart failure, septic shock, asthma, and Alzheimer""s disease. Compounds of the invention are also useful as antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). The methods include administering to a patient in need of such treatment, or suffering from such a disease or condition, a pharmaceutically effective amount of a disclosed compound or pharmaceutical composition thereof.
The invention also features methods of combination therapy, such as a method for treating cancer, wherein the method further includes providing radiation therapy or chemotherapy, for example, with mitotic inhibitors such as a taxane or a vinca alkaloid. Examples of mitotic inhibitors include paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine. Other therapeutic combinations include a MEK inhibitor of the invention and an anticancer agent such as cisplatin, 5-fluorouracil or 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide, and gemcitabine.
The chemotherapy or radiation therapy may be administered before, concurrently, or after the administration of a disclosed compound according to the needs of the patient.
The invention also features synthetic intermediates and methods disclosed herein.
Other aspects of the invention are provided in the description, the examples, and the claims below.